Abstract
BackgroundStatin treatment of hypercholesterolemia is accompanied also with depletion of the mevalonate intermediates, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) necessary for proper function of small GTPases. These include Ras proteins, prevalently mutated in pancreatic cancer. In our study, we evaluated the effect of three key intermediates of the mevalonate pathway on GFP-K-Ras protein localization and the gene expression profile in pancreatic cancer cells after exposure to individual statins.MethodsThese effects were tested on MiaPaCa-2 human pancreatic cancer cells carrying a K-Ras activating mutation (G12C) after exposure to individual statins (20 μM). The effect of statins (atorvastatin, lovastatin, simvastatin, fluvastatin, cerivastatin, rosuvastatin, and pitavastatin) and mevalonate intermediates on GFP-K-Ras protein translocation was analyzed using fluorescence microscopy. The changes in gene expression induced in MiaPaCa-2 cells treated with simvastatin, FPP, GGPP, and their combinations with simvastatin were examined by whole genome DNA microarray analysis.ResultsAll tested statins efficiently inhibited K-Ras protein trafficking from cytoplasm to the cell membrane of the MiaPaCa-2 cells. The inhibitory effect of statins on GFP-K-Ras protein trafficking was partially prevented by addition of any of the mevalonate pathway’s intermediates tested. Expressions of genes involved in metabolic and signaling pathways modulated by simvastatin treatment was normalized by the concurrent addition of FPP or GGPP. K-Ras protein trafficking within the pancreatic cancer cells is effectively inhibited by the majority of statins; the inhibition is eliminated by isoprenoid intermediates of the mevalonate pathway.ConclusionsOur data indicate that the anticancer effects of statins observed in numerous studies to a large extent are mediated through isoprenoid intermediates of the mevalonate pathway, as they influence expression of genes involved in multiple intracellular pathways.
Highlights
Statin treatment of hypercholesterolemia is accompanied with depletion of the mevalonate intermediates, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) necessary for proper function of small GTPases
This statinmediated action was completely eliminated by an excess of mevalonate (Fig. 1, column B), indicating that this biologically important effect of statins is due to the inhibition of the mevalonate pathway
The effect of FPP and GGPP on simvastatin-mediated changes in the gene expression of MiaPaCa-2 human pancreatic cancer cells Overall numbers of genes with significant changes in expression after simvastatin, FPP, or GGPP treatment of MiaPaCa-2 human pancreatic cancer cells are listed in Additional file 2: Table S2
Summary
Statin treatment of hypercholesterolemia is accompanied with depletion of the mevalonate intermediates, including farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP) necessary for proper function of small GTPases These include Ras proteins, prevalently mutated in pancreatic cancer. The K-Ras signaling pathway is of special importance in pancreatic cancer, since >90% of these tumors bear activating mutations in K-Ras oncogene [8] This oncogenic signaling pathway in pancreatic cancer is complex and passes through three major effector branches: Raf/ Mek/Erk, PI3K/Pdk1/Akt and the Ral guanine nucleotide exchange factor pathway [9]. Because of this widespread effects, the K-Ras signaling pathway is a promising target in pancreatic cancer and various novel therapeutic approaches to suppress K-Ras signaling are currently under investigation. Despite these comprehensive efforts, effective anti-Ras drugs have yet to reach the clinic [10]
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